ABSTRACT
Liposomes represent one of the most clinically advanced drug-delivery systems with the range of medical applications extending from chemotherapy of cancer and infectious disease to vaccines and gene therapy (1,2). However, liposomal formulations of genetic drugs such as antisense oligonucleotides and plasmidDNA (pDNA) for systemic applications are difficult to achieve (3). The large size and highly-charged nature of these molecules mitigates against the formation of small, neutral, serum-stable carriers, which are required to achieve the long circulation times necessary for efficient accumulation at disease sites such as sites of tumor growth and inflammation. In particular, passive encapsulation of pDNA in liposomes is very inefficient due to the large size of these molecules. Efficient entrapment requires interaction between the lipid components of the carrier and the nucleotide-based drugs. However, this interaction is very difficult to control. For example, complexes formed through electrostatic interaction between negatively-charged polynucleotides and cationic liposomes exhibit broad size distributions. These complexes efficiently transfect cells in vitro; however, in vivo their large size and/or positive charge triggers rapid clearance from the circulation (4-8). They can also be highly toxic (8). Therefore, substantial effort has been focused on constructing lipid-based carriers with improved in vivo characteristics.
